Expression of a dominant negative c-jun under constitutive or inducing conditions inhibits ap-1 and nfkb, and reverses tumor phenotype in transformed human keratinocvtes

Jian-Jian Li, Ya Cao, Nancy H. Colburn

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Elevation of both AP-I and NFkB transactivation has been observed by us and appears to be required for signaling cell transformation in mouse skin JB6 and mouse keratinocyte neoplastic progression models. We now report that forced expression of a dominant negative mutant c-jun (TAM67) gene controlled by a constitutive promoter, human keratin 14, inhibits the elevated uansaciivauon of both factors (67%-73% for AP-1 and 66%-81% for NFkB respectively) and anchorage-independent proliferation (50%) in HPV16 E6/E7 or HPV18/v-fos transformed human kcratinocytes. In order to analyze tumor phcnotypc reversion by TAM67 in a tetracycline regulated system in which higher levels transgemc expression might be achieved, pTRB-TAM67 was co-transfectcd with tet-regulator tTA into v-fos transformed human kcratinocyrc Une ISv-fos. The results showed that both AP-1 and NFkB traiuactivation but not that of p53 were inhibited by induced TAM67 expression. Morphological appearance and growth rate of HPV18v-fos cells under TAM inducing conditions were indistinguishable from those under non inducing conditions. HPV E7 expression level was not changed by induction of TAM expression, ihus excluding E7 change as a possible mediator of reversion. Over 90% inhibition of anchorage-independent growui was observed in the stable TAM gene iransfcciants under inducing conditions. These observations indicate that elevation of both AP-1 and NFkB are involved in maintenance of lumor pUenotype in HPV E6;E7/v.fos transformed human kcratinocytcs. Targeting AP-1 and/or NFkB transactivation serves to suppress tumor phenotype without producing adverse side effects. Inhibition of both transcription factors and expression of malignant phenotype by the dominant negative jun gene using inducible constructs may offer potential for tumor gene therapy.

Original languageEnglish (US)
JournalFASEB Journal
Issue number8
StatePublished - 1998
Externally publishedYes


ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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